Novel pharmaceutical compositions of β-blockers with diuretics

ABSTRACT

Compositions containing substituted 1,2,5 thiadiazole β-blocking agent and pyrazine and/or thiazide diuretic, and a method of treating hypertensive animals are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 734,702, filed Oct. 21, 1976which in turn is a continuation-in-part of U.S. application Ser. No.554,373, filed Mar. 3, 1975, now abandoned, which in turn is acontinuation-in-part of U.S. Application Ser. No. 497,961 filed Aug. 16,1974 now abandoned.

BACKGROUND OF THE INVENTION

Diuretics such as the thiazides and pyrazines are useful asantihypertensive agents. However, these diuretics tend to increasecirculating plasma renin levels. This increase in renin may beundesirable since it acts to reduce the antihypertensive effect of thediuretic.

β-adrenergic blocking agents are another class of drugs which areeffective in long term treatment of hypertension. Propranalol, aβ-adrenergic blocking agent, has been found to inhibit renal reninsecretion in man and in animals [New England Journal of Medicine 287,1209-1213 (1972)] Pindolol, another β-adrenergic blocking agent, hasbeen found to have antihypertensive effect when administered alone andin combination with a thiazide diuretic [The Medical Journal ofAustralia 2, 309-312, (1972)]. The effect on hypertension of acombination of large doses of 4 different β-blocking agents (including asubstituted 1,2,5-thiadiazole) with a thiazide diuretic, has also beenreported (Postgraduate Medical Journal 50, 253-259, May, 1974).

It has been discovered that administration of a particular combinationof a substituted 1,2,5 thiadiazole β-adrenergic blocking agent and saiddiuretic to a hypertensive animal (1) enhances the antihypertensiveactivity of the diuretic and (2) reduces the severity of potassium lossdue to the diuretic.

SUMMARY OF THE INVENTION

Composition comprising (1) a substituted 1,2,5-thiadiazole β-blockingagent and (2) a thiazide and/or pyrazine diuretic; and a method oftreating a hypertensive animal.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment of the present invention are compositions containing:

(A) β-blocking agents selected from:

(i) compounds having the formula ##STR1## wherein R is selected fromhydrogen, halogen, C₃ -C₆ cycloalkyl, C₁ -C₄ alkyl, C₂ -C₄ alkenyl,phenyl, substituted phenyl, C₁ -C₅ alkoxy, heterocycle, C₁ -C₄alkylcarbamoyl, carbamoyl and R² --L--R³ -- wherein R² is selected fromC₁ -C₃ alkyl, phenyl and substituted phenyl, L is selected from oxygenand sulfur and R³ is methyl or ethyl; and R' is selected from C₁ -C₁₀alkyl, C₂ -C₆ alkynyl, C₂ -C₄ alkenyl, C₃ -C₆ cycloalkyl, C₁ -C₄alkylthio, and heterocycle.

(ii) non-toxic pharmaceutically acceptable salts of (i); and

(iii) mixtures containing (i) and (ii); and

(B) diuretic selected from:

(a) thiazides and their pharmaceutically acceptable salts

(b) amiloride and its pharmaceutically acceptable salts and

(c) mixtures of (a) and (b).

The β-blocking agents of the Formula I include the individual opticalisomers as well as the racemate. More preferred Formula I compounds andsalts are those wherein R is hydrogen; halogen such as chlorine,bromine, fluorine and the like; alkyl such as methyl, ethyl, propyl,t-butyl and the like; alkenyl such as vinyl, allyl, methallyl and thelike: R² --L--R³ -- radical wherein R² is alkyl such as methyl, ethyl,propyl; phenyl or substituted phenyl wherein the substituents areselected from the group consisting of halogen such as chlorine, bromine,fluorine and the like, hydroxy, alkyl such as methyl, ethyl, propyl andthe like, or alkoxy such as methoxy, ethoxy, propoxy and the like; L isoxygen or sulfur and R³ is alkyl such as methyl and ethyl; carbamoyl;alkylcarbamoyl wherein the alkyl moiety is represented by methyl, ethyl,isopropyl, butyl and the like; cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like; alkoxy such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and the like;phenyl or substituted phenyl wherein the substituents are selected fromthe group consisting of one or more halogen such as chlorine, fluorineand the like, alkyl having from 1 to 3 carbons, and alkoxy having from 1to 3 carbons, aralkyl wherein the alkyl moiety has from 1 to 4 carbonsand the aryl moiety can be unsubstituted or substituted with one or morehalogen such as chlorine, fluorine, bromine and the like, alkyl havingfrom 1 to 3 carbons, or alkoxy having from 1 to 3 carbons; and aheterocyclic moiety such as aziridinyl, azetidinyl, pyrrolidyl,piperidyl, hexahydro-azepineo, morpholino, piperidino, thiazolidinyl,p-thiazinyl, piperazinyl, thienyl, furyl and the like; R' is alkylhaving from 1 up to about 10 carbons, preferably 1 to 6 carbons and morepreferably from 3 to 6 carbons such as isopropyl, tert-butyl,2,2-dimethylpropyl, hexyl and the like; alkenyl such as allyl, vinyl,methalkyl and the like; or alkynyl groups having from 2 to 6 carbons,such as --C═CH, propynyl, butynyl, propargyl, hexynyl and the like;substituted alkyl wherein the substituents are selected from the groupconsisting of hydroxy and halogen such as chlorine, bromine and thelike; carboxy; alkoxy; alkylthio wherein the alkyl moiety contains from1 to 4 carbons; cycloalkyl such as cyclopropyl, cyclohexyl, cyclopentyland the like; and a heterocyclic group such as pyrrolidinyl,piperazinyl, morpholino, thiazolidinyl, thienyl, furyl, thiazinyl andthe like.

Formula I compounds where R is morpholino, piperidino orhydroxypiperidino are more preferred--and particularly preferred are theFormula I compounds where R is morpholino, piperidino, hydroxypiperidinoand R' is C₁ -C₁₀ alkyl.

Representative Formula I compounds and their salts which are useful inthis invention are:

3-chloro-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

(+)-3-chloro-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadazolehydrocyloride

3-bromo-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

(-)-3-bromo-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride

3-(4-hydroxypiperidino)-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

3-morpholino-4-(3-n-hexylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrogen maleate

(+)-3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrogen maleate

(-)-3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrogen maleate

3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride

3-N-t-butylcarbamoyl-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

(+)-3-N-t-butylcarbamoyl-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride

(-)-3-N-t-butylcarbamoyl-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride

3-N-isopropylcarbamoyl-4-(3-isopropylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

(+)-3-N-isopropylcarbamoyl-4-(3-isopropylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride

(-)-3-N-isopropylcarbamoyl-4-(3-isopropylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride

3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolebenzoate

3-chloro-4-(3-isopropylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

3-bromo-4-(3-isopropylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

(+)-3-chloro-4-(3-isopropylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

3-methyl-4-(3-n-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

3-ethoxy-4-(3-sec-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole

and the like.

Especially preferred Formula I compounds are those in which R ishalogen, alkyl, alkoxy, phenyl, benzyl, morpholino, piperazino andpiperidino and R' is alkyl, preferably C₃ -C₆. A most preferred FormulaI compound is one where R is morpholino, R' is t-butyl, and moreparticularly the (-)isomer and pharmaceutically acceptable saltsthereof, especially the hydrogen maleate.

The pharmaceutically acceptable salts of Formula I compounds areincluded as useful compounds in the present invention. Any non-toxic,pharmaceutically acceptable salt of Formula I compounds may be used.Representative examples of these pharmaceutically acceptable salts arethe hydrohalides, e.g., hydrochlorides, hydrobromides, hydroiodides; thephosphates, sulfates, oxalates, lactates, malates, maleates, formates,acetates, succinates, tartrates, salicylates, citrates, phenylacetates,benzoates, p-toluene-sulfonates and other salts such as those thatprovide relatively insoluble products that afford a slow release of theactive material, for example, a1,1'-methylene-bis-(2-hydroxy-3-naphthoate) and the like.

The β-blocking agent of Formula I and methods for their preparation aredescribed in U.S. Pat. Nos. 3,655,663, 3,729,469, 3,657,237, 3,718,647and 3,812,182. To the extent necessary, the disclosure of said patentsis incorporated herein by reference.

The diuretics used in the present invention include (a) thiazides andtheir non-toxic pharmaceutically acceptable salts (b) pyrazine and itsnon-toxic pharmaceutically acceptable salts, and (c) mixtures of (a) and(b).

The thiazides comprise a 1,2,4 benzothiadiazine class of compounds. Theyinclude compounds such as flumethiazide, benzthiazide, cyclopenthiazide,cyclothiazide, trichloromethiazide, benzhydroflumethiazide,methylcyclothiazide, polythiazide, thiabutazide, and the like and theirnon-toxic, pharmaceutically acceptable salts.

Preferred thiazides are those having the following formulae: ##STR2##and their pharmaceutically acceptable salts.

The Formula II compound is chlorothiazide and the Formula III compoundis hydrochlorothiazide. Salts of the Formula II and III compoundsinclude those of alkali metals, especially sodium.

The thiazide diuretics, their use and methods for their preparation aredescribed in U.S. Pat. Nos. 2,809,194, 3,025,292, 2,937,169, 3,164,588and 3,043,840. The information in these patents is incorporated hereinby reference.

The pyrazine diuretic has the formula ##STR3##

The Formula IV compound is amiloride. The compound and its preparationare described in Belgian Pat. No. 639,386. Amiloride is also useful as anon-toxic pharmaceutically acceptable salt of inorganic acid, e.g.,hydrohalo acid, phosphorus acid, sulfuric acid and the like, and organicacid e.g., citric, tartaric, maleic, sulfonic, phosphonic, malic,acetic, and the like. A most preferred salt of amiloride is thehydrochloride dihydrate.

Combinations containing thiazide and pyrazine diuretics are also useful.The weight ratios of the diuretics in these combinations can be varied.Generally weight ratios of diazine:thiazide from 1:1 to 1:10 are usefuland a weight ratio of 1:10 is particularly useful. In a preferredcombination the diazine is amiloride hydrochloride (or its dihydrate)and the thiazide hydrochlorothiazide--and in a most preferredcombination the weight ratio of said amiloride; said hydrochlorothiazideis 1:10. These combinations are disclosed in U.S. Pat. No. 3,781,430.

The compositions of the present invention are administered in dosequantities of β-adrenergic blocking agent: diuretic in weight ratio offrom about 1:15 to about 24:1, preferably about 1:12 to about 4:1 andmore preferably about 1:1 to about 4:1 and most preferably about 1:1 toabout 1:10; a 1:1.25-1:5 ratio range is especially preferred. The amountof β-adrenergic blocking agent and diuretic administered is varied.Generally, the β-blocking agent is administered in quantities rangingfrom 1-12 mg. per kilogram of animal body weight while the diuretic isadministered in quantities ranging from about 0.5-15 mg. per kilogram ofanimal body weight. A preferable administration quantity range for theβ-blocking agent is about 1-8 mg./kg/day and for the diuretic about 1-10mg./kg./day. The present compositions are useful for treatinghypertension in animals (patients) to effect a decrease in bloodpressure. These compositions are administered in varying dosages and forvarious periods of time as the treatment requires.

It is to be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, rate of excretion,drug combination and the severity of the disease undergoing therapy.

The compositions of the present invention may be administered in anyacceptable and recognized manner. They are preferably administeredorally in an acceptable dosage form. The compounds may be combined in acapsule. The compositions may be provided in the form of tablets; saidtablets may include other ingredients which are ordinarily used tofacilitate tablet formation, palatability, etc. The compositions maylikewise be dissolved or dispersed in a pharmaceutically acceptablecarrier for administration in a fluid form.

The following examples illustrate but do not limit the preparation ofthe various compositions of the invention.

                  TABLE I                                                         ______________________________________                                                      Ex.    Ex.    Ex.  Ex.  Ex.  Ex.                                Ingredients   1      2      3    4    5    6                                  ______________________________________                                        3-morpholino-4-(3-t-                                                                         10     10     10   5    5    5                                 butylamino-2-hydroxy-                                                         propoxy)-1,2,5-thia-                                                          diazole                                                                       Hydrochlorothiazide                                                                          10     25     50  10   25   50                                 Starch USP Corn                                                                             124    114    109  99   84   80                                 Microcrystalline                                                                            134    129    109  85   85   54                                 Cellulose                                                                     Magnesium Stearate                                                                           2      2      2    1    1    1                                 TOTAL (mg./tablet)                                                                          280    280    280  200  200  200                                ______________________________________                                    

3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole,hydrochlorothiazide, part of the corn starch and microcrystallinecellulose are mixed together, milled and granulated with part of thecorn starch as starch paste. The granulated mass is wet-sized, dried,dry milled, and blended with the remaining corn starch andmicrocrystalline cellulose, lubricated with magnesium stearate, andcompressed in to tablets.

Equivalent amounts of chlorothiazide or its sodium salt may besubstituted for the hydrochlorothiazide in the Table I formulation toprepare corresponding compositions.

When other β-adrenergic blocking agents such as3-chloro-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole,3-(4-hydroxypiperidino)-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole,3-piperazino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole,3-piperidino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole,3-N-isopropylcarbamoyl-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole,3-N-isopropylcarbamoyl-4-(3-isopropyl-amino-2-hydroxypropoxy)-1,2,5-thiadiazole,3-methyl-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole,3-ethoxy-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole orrepresentative salt thereof is substituted for3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole,there is obtained the corresponding composition.

                  TABLE II                                                        ______________________________________                                                      Ex.    Ex.    Ex.  Ex.  Ex.  Ex.                                Ingredients   7      8      9    10   11   12                                 ______________________________________                                        3-morpholino-4-                                                                              10     10     10   5    5    5                                 (3-t-butylamino-2-                                                            hydroxypropoxy)-1,                                                            2,5-thiadiazole                                                               hydrogen maleate                                                              Hydrochlorothiazide                                                                          10     25     50  10   25   50                                 Starch USP Corn                                                                             124    114    109  99   84   80                                 Microcrystalline                                                                            134    129    109  85   85   54                                 Cellulose                                                                     Magnesium Stearate                                                                           2      2      2    1    1    1                                 TOTAl (mg./tablet)                                                                          280    280    280  200  200  200                                ______________________________________                                    

3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrogen maleate, hydrochlorothiazide, part of the corn starch andmicrocrystalline cellulose are mixed together, milled and granulatedwith part of the corn starch as starch paste. The granulated mass iswet-sized, dried, dry milled, and blended with the remaining corn starchand microcrystalline cellulose, lubricated with magnesium stearate, andcompressed into tablets.

Corresponding compositions are prepared when an equivalent amount ofamiloride or its hydrochloride dihydrate is substituted forhydrochlorothiazide in Table II.

When other optically active β-adrenergic blocking agents such as(-)-3-chloro-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride,(-)-3-(4-hydroxypiperidino)-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride,(-)-3-piperidino)-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrogen maleate,(-)-3-N-t-butylcarbamoyl-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride,(-)-3-methyl-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride,(-)-3-ethoxy-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride or(-)-3-chloro-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole issubstituted for3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrogen maleate, there is obtained the corresponding composition.

                  TABLE III                                                       ______________________________________                                                      Ex.    Ex.    Ex.  Ex.  Ex.  Ex.                                Ingredients   13     14     15   16   17   18                                 ______________________________________                                        3-morpholino-4-                                                                              10     10     10   5    5    5                                 3-t-butylamino-2-                                                             hydroxypropoxy)-1,2,                                                          5-thiadiazole hydro-                                                          gen maleate (racemate)                                                        Hydrochlorothiazide                                                                          10     25     50  10   25   50                                 Starch USP Corn                                                                             124    114    109  99   84   80                                 Microcrystalline                                                                            134    129    109  85   85   54                                 Cellulose                                                                     Magnesium Stearate                                                                           2      2      2    1    1    1                                 TOTAL (mg./tablet)                                                                          280    280    280  200  200  200                                ______________________________________                                    

(3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrogen maleate (racemate), hydralazine, part of the corn starch andmicrocrystalline cellulose are mixed together, milled and granulatedwith part of the corn starch as starch paste. The granulated mass iswet-sized, dried, dry milled, and blended with the remaining corn starchand microcrystalline cellulose, lubricated with magnesium stearate, andcompressed into tablets.

A mixture containing hydrochlorothiazide and amiloride hydrochloridedihydrate are substituted for hydrochlorothiazide in Table III toprepare corresponding compositions.

When other optically active β-adrenergic blocking agents such as racemic3-chloro-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride,(-)-3-(4-hydroxypiperidino)-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolecitrate,(+)-3-piperidino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride, racemic3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrobromide,(+)-3-N-t-butylcarbamoyl-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrochloride,(-)-3-methyl-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazoleacetate,(+)-3-ethoxy-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolephosphate, or(+)-3-chloro-4-(3-t-butylamino-2-hydroxybutoxy)-1,2,5-thiadiazolehydrochloride is substituted for racemic3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrogen maleate, with the hydrochlorothiazide or mixedhydrochlorothiazide/amiloride HCl.2H₂ O corresponding compositions areobtained.

The effect of the compositions of the present invention on bloodpressure and plasma potassium was determined by an in vivo procedureutilizing adult beagle dogs in which hypertension was produced bysurgical modification of the kidney. The blood pressure and plasmapotassium level of these hypertensive dogs were measured over a numberof days before and after (twice a day) oral administration (in gelatincapsule) of hydrochlorothiazide (HCTZ) and a combination of HCTZ and(-)-3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazolehydrogen maleate (MTHM). The results obtained from a statisticallydesigned set of experiments, using the aforesaid procedure, aretabulated below:

                  TABLE A                                                         ______________________________________                                        EFFECT ON BLOOD PRESSURE AND PLASMA POTASSIUM                                                             Days                                                                   No.    of    Plasma.sub.1                                                                         Blood.sub.2                                               of     Treat-                                                                              Po-    Pres-                                Test Treatment       Dogs   ment  tassium                                                                              sure                                 ______________________________________                                        A 1  Control         5      --    4.2    140                                  2    HCTZ-10 mg/kg/day                                                                             5      2     3.4    122                                  3    HCTZ-10 mg/kg/day                                                                             5      4     3.6    129                                  D 1  Control         5      --    4.3    132                                  2    HCTZ-10 mg/kg/day                                                                             5      2     4.1    114                                       +                                                                             MTHM-2.0 mg/kg/day                                                       3    HCTZ-10 mg/kg/day                                                                             5      4     4.1    105                                       MTHM-2.0 mg/kg/day                                                       B 1  Control (lactose)                                                                             4      --    --     126                                  2    MTHM-1.0 mg/kg/day                                                                            4      2     --     128                                       MTHM-1.0 mg/kg/day                                                                            4      4     --     133                                  3    MTHM-4.0 mg/kg/day                                                                            4      2     --     137                                       MTHM-4.0 mg/kg/day                                                                            4      4     --     141                                  C 1  Control         6      3     4.5    --                                        MTHM-2.0 mg/kg/day                                                                            12     3     5.0    --                                   ______________________________________                                         .sub.1 millequivalents/liter                                                  .sub.2 mean arterial in mm/Hg                                            

Comparable results were obtained when comparing effect on blood pressureand plasma potassium of 2.5 mg./kg/day HCTZ with 2.5 mg./kg/day HCTZ+2mg./kg/day MTHM and 2.5 mg./kg/day HCTZ+8 mg./kg/day MTHM. The datapresented in Table A, clearly shows that the substituted thiadiazolesubstantially enhances (1) the antihypertensive effect ofhydrochlorothiazide and (20 reduces the severity of potassium lossproduced by hydrochlorothiazide.

Other combinations and dosages which have been studied are MTHM/HCTZ at1.0/2.5, 4.0/10.0 and 8.0/10.0 mg/kg/day; and MTHM/HCTZ/amiloridehydrochloride dihydrate at 1.0/2.5/0.25, 4.0/10.0/1.0, 8.0/10.0/1.0, and10.0/25/2.5 mg/kg/day. Tablets containing 10 mg MTHM/25 mg HCTZ or 10 mgMTHM/25 mg HCTZ/2.5 mg amiloride hydrochloride dihydrate administeredtwice a day, orally, to hypertensive humans have been shown to beeffective.

In addition to blood pressure reduction and plasma potassium levelmaintained the HCTZ/MTHM compositions were also found to reducecirculating renin levels.

Analogous results are obtained for other compositions of the presentinvention as disclosed herein. Claims to the invention follow.

What is claimed is:
 1. A method of treating a hypertensive animal toreduce blood pressure which comprises administration to said animal of ablood pressure reducing amount of a composition comprising:(A)β-blocking agent selected from:(i) compounds having the formula ##STR4##wherein R is morpholino and R' is selected from C₁ -C₁₀ alkyl, C₂ -C₆alkynyl, C₂ -C₄ alkenyl, C₁ -C₄ alkylthio, C₃ -C₆ cycloalkyl andheterocycle (ii) non-toxic pharmaceutically acceptable salt of (i); and(iii) mixtures containing (i) and (ii); and (B) diuretic mixturecontaining(a) thiazides or their pharmaceutically acceptable salt and(b) amiloride or its pharmaceutically acceptable saltwherein the weightratio of (A):(B) is about 1:1 to about 1:10.
 2. The method of claim 1wherein R' is C₁ -C₆ alkyl.
 3. The method of claim 2 wherein R' ist-butyl and said β-blocking agent is said (ii) salt of the (i)(-)isomer.
 4. The method of claim 3 wherein said (ii) salt is thehydrogen maleate and said diuretic mixture is amiloride hydrochloridedihydrate and hydrochlorothiazide.
 5. The method of claim 4 wherein saidsaid diuretic mixture contains about 10 parts by weighthydrochlorothiazide and about 1 part by weight amiloride hydrochloridedihydrate.
 6. Composition comprising:(A) β-blocking agent selectedfrom:(i) compounds having the formula ##STR5## wherein R is morpholinoand R' is selected from C₁ -C₁₀ alkyl, C₂ -C₆ alkynyl, C₂ -C₄ alkenyl,C₁ -C₄ alkylthio, C₃ -C₆ cycloalkyl and heterocycle, (ii) non-toxicpharmaceutically acceptable salt of (i); and (iii) mixtures containing(i) and (ii); and (B) diuretic mixture containing(a) a1,2,4-benzothiadiazine or their pharmaceutically acceptable salt, and(b) amiloride or its pharmaceutically acceptable saltwherein the weightration of (A):(B) is about 1:1 to about 1:10.
 7. Composition of claim 6wherein said thiazide component is selected from chlorothiazide, alkalimetal salts of chlorothiazide, and hydrochlorothiazide.
 8. Compositionof claim 1 wherein said diuretic is said (b).
 9. Composition of claim 7wherein R' is t-butyl and said β-blocking agent is said (ii) salt of the(i) (-) isomer.
 10. Composition of claim 9 wherein said (ii) salt is thehydrogen maleate and said diuretic component b is amiloridehydrochloride dihydrate.
 11. Composition of claim 7 wherein R' ist-butyl, said β-blocking agent is said (ii) salt of the (i) (-)-isomer.12. Composition of claim 11 wherein said (ii) salt is the hydrogenmaleate and said diuretic mixture contains about 10 parts by weighthydrochlorothiazide and about 1 part by weight amiloride hydrochloridedihydrate.
 13. Composition comprising(A) β-blocking agent selected fromthe group consisting of(i) compound having the formula ##STR6## whereinR is morpholino and R' is C₁ -C₁₀ alkyl; (ii) non-toxic pharmaceuticallyacceptable salt of (i); and (iii) mixtures containing (i) and (ii); and(B) diuretic mixture containing(a) hydrochlorothiazide, chlorothiazideor their pharmaceutically acceptable salt, and (b) amiloride or itspharmaceutically acceptable saltwherein the weight ratio; of (A):(B) isabout 1:1 to about 1:10.
 14. Composition of claim 13 wherein R' is C₃-C₆ alkyl.
 15. Composition of claim 14 wherein said (B) (a) component ishydrochlorothiazide and said (B) (b) component is amiloridehydrochloride dihydrate.
 16. Composition of claim 15 wherein the weightratio of (B) (a):(B) (b) is about 10:1.
 17. Composition of claim 16wherein said β-blocking agent is a salt of (-) isomer of the formula##STR7## and the weight ratio of said β-blockingagent:hydrochlorothiazide; amiloride hydrochloride dihydrate is about4:10:1 to about 8:10:1.
 18. The composition of claim 17 wherein saidβ-blocker salt is the hydrogen maleate and said ratio is 4:10:1. 19.Composition of claim 6 wherein said thiazide is flumethiazide,benzthiazide, cyclopenthiazide, cyclothiazide, trichloromethiazide,benzhydroflumethiazide, methylcyclothiazide, polythiazide, thiabutazideor pharmaceutically acceptable salts thereof.
 20. Composition of claim 6wherein said thiazide is benzhydroflumethiazide.